Alcoholism is a common comorbid condition of HIV infection. Both conditions have been independently associated with significant brain damage. Mounting evidence suggests that excessive alcohol use may exacerbate HIV-associated brain damage, yet few studies are available that directly address their combined effects. The proposed research will examine the structural and functional brain integrity in HIV-infected individuals and HIV seronegative controls with and without history of heavy alcohol use. Specifically, Diffusion tensor imaging will be used to examine the integrity of brain white matter and structural connectivity. Functional MRI will be used to examine functional brain response to cognitive task. In addition, an exploratory analysis of functional connectivity based on BOLD/FMRI data will provide additional measures of brain connectivity. Using this novel approach of combining multiple neuroimaging and neurocognitive measures, the study will help achieve a better understanding of how functional cortical brain abnormality and neurocognitive impairment associated with alcohol use and HIV infection are linked to degradation of white matter pathways that connect these brain regions. The applicant has received extensive training in neuroimaging investigation of HIV- associated brain dysfunction. The proposed training and research plans represents a natural extension of his work to examine the impact of alcohol use on HIV-associated brain dysfunction, utilizing multiple MRI modalities. To achieve the goal of conducting independent research in this area, the K99 training plan will emphasize 1) the behavioral and biological consequences of alcohol use, 2) the analysis and application of BOLD/FMRI data, and 3) advancing the applicant's current knowledge in neuroAIDS and analysis of diffusion- weighted MRI data. A comprehensive training plan is proposed, combining mentored research and structured didactic activities guided by established researchers in the field, formal coursework and workshops, and participation in seminars at Brown University and The Miriam Hospital. PUBLIC HEALTH RELEVANCE: Results from this study will promote a better understanding of the biological mechanisms underlying alcohol/HIV-related neurocognitive dysfunction, which will help to guide behavioral and pharmacological interventions. In addition, the novel neuroimaging measures may serve as more sensitive biomarkers than those currently available for identifying individuals at risk for neurocognitive dysfunction. Ultimately, successful prevention and treatment of neurocognitive deficits will to help to improve the quality of life and health outcome of HIV-infected individuals.